Phosphorylation of Tip60 by GSK-3 Determines the Induction of PUMA and Apoptosis by p53

Activation of p53 by DNA damage results in either cell-cycle arrest, allowing DNA repair and cell survival, or induction of apoptosis. As these opposite outcomes are both mediated by p53 stabilization, additional mechanisms to determine this decision must exist. Here, we show that glycogen synthase...

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Bibliographic Details
Published in:Molecular cell 2011-06, Vol.42 (5), p.584-596
Main Authors: Charvet, Céline, Wissler, Manuela, Brauns-Schubert, Prisca, Wang, Shang-Jui, Tang, Yi, Sigloch, Florian C., Mellert, Hestia, Brandenburg, Martin, Lindner, Silke E., Breit, Bernhard, Green, Douglas R., McMahon, Steven B., Borner, Christoph, Gu, Wei, Maurer, Ulrich
Format: Article
Language:English
Subjects:
Acetylation
Apoptosis - physiology
Apoptosis Regulatory Proteins - metabolism
Cell Line, Tumor
DNA Damage
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 - physiology
Histone Acetyltransferases - chemistry
Histone Acetyltransferases - metabolism
Histone Acetyltransferases - physiology
Humans
Lysine Acetyltransferase 5
Phosphorylation
Promoter Regions, Genetic
Proto-Oncogene Proteins - metabolism
Tumor Suppressor Protein p53 - physiology
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Summary:Activation of p53 by DNA damage results in either cell-cycle arrest, allowing DNA repair and cell survival, or induction of apoptosis. As these opposite outcomes are both mediated by p53 stabilization, additional mechanisms to determine this decision must exist. Here, we show that glycogen synthase kinase-3 (GSK-3) is required for the p53-mediated induction of the proapoptotic BH3 only-protein PUMA, an essential mediator of p53-induced apoptosis. Inhibition of GSK-3 protected from cell death induced by DNA damage and promoted increased long-term cell survival. We demonstrate that GSK-3 phosphorylates serine 86 of the p53-acetyltransferase Tip60. A Tip60S86A mutant was less active to induce p53 K120 acetylation, histone 4 acetylation, and expression of PUMA. Our data suggest that GSK-3 mediated Tip60S86 phosphorylation provides a link between PI3K signaling and the choice for or against apoptosis induction by p53. ► PUMA and apoptosis induction by p53 require GSK-3 ► GSK-3 phosphorylates the acetyltransferase Tip60 on Serine 86 ► Tip60S86A exhibits diminished acetylation of p53 at K120, H4, and expression of PUMA ► Acetylation of H4 at the puma promoter depends on GSK-3 and p53
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2011.03.033